This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. When activated and associated with appropriate members of a functional complex, the mammalian target of rapamycin (mTOR) plays an important role in regulation of protein synthesis, cell growth, and proliferation. mTOR inhibitors have the potential to augment the activity of conventional chemotherapeutic drugs, including those frequently used in the treatment of pediatric malignancies. In this Phase I study, the mTOR inhibitor temsirolimus will be administered in combination with irinotecan and temozolomide to patients with recurrent or refractory solid tumors. The irinotecan + temozolomide regimen has activity against solid tumors including Ewing sarcoma and neuroblastoma. Toxicity associated with this regimen has been relatively mild even in heavily pretreated patients. The limited overlap in toxicities associated with temsirolimus and with rinotecan + temozolomide suggests that this three drug regimen is likely to be well-tolerated. Irinotecan (50 mg/m2) and temozolomide (100 mg/m2) will be administered daily x 5 every 3 weeks. Temsirolimus will be administered on days 1 and 8 of each 3 week cycle. The starting dose of temsirolimus will be 15 mg/m2, and the dose of this agent will be escalated stepwise to a maximum dose of 35 mg/m2 on Days 1 and 8. Because the primary objective of the study is to determine the maximum dose of temsirolimus that can be administered in combination with widely used doses of irinotecan and temozolomide, doses of the irinotecan and temozolomide will not be escalated during this trial. If the administration of temsirolimus on Days 1 and 8 is not well tolerated when given in combination with irinotecan and temozolomide, then temsirolimus will be administered once per cycle only. Patients will be accrued to dose levels in cohorts of 2 to 6 using the Rolling Six Phase I trial design. There will be no intrapatient dose escalation. Toxicity will be graded using the CTCAE version 4.0 and response will be assessed using RECIST criteria. Optional laboratory analyses of modulation of mTOR pathway signaling will be conducted using tumor-containing bone marrow samples from consenting patients.